Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver fibrosis

Title
Liver sinusoidal endothelial cell expressed vascular cell adhesion molecule 1 promotes liver fibrosis
Publication Date
2022-08-25
Author(s)
Guo, Qianqian
Furuta, Kunimaro
Islam, Shahidul
( author )
OrcID: https://orcid.org/0000-0001-8984-8689
Email: mislam27@une.edu.au
UNE Id une-id:mislam27
Caporarello, Nunzia
Kostallari, Enis
Dielis, Kobe
Tschumperlin, Daniel J
Hirsova, Petra
Ibrahim, Samar H
Type of document
Journal Article
Language
en
Entity Type
Publication
Publisher
Frontiers Research Foundation
Place of publication
Switzerland
DOI
10.3389/fimmu.2022.983255
UNE publication id
une:1959.11/70418
Abstract

Background: During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis.

Methods: Wild-type C57BL/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (Vcam1Δend) and control mice (Vcam1fl/fl) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from Vcam1fl/fl or Vcam1Δend and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a μ-Slide 2 well co-culture system.

Results: Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in Vcam1fl/fl mice and restored in Vcam1Δend mice in both NASH and liver fibrosis models. Co-immunostaining showed increased α-smooth muscle actin in the livers of Vcam1fl/fl mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the Vcam1fl/fl mice but not Vcam1Δend mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed Vcam1Δend mice compared to Vcam1fl/fl mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs in vitro, supporting the profibrogenic role of LSEC VCAM1.

Conclusion: VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.

Link
Citation
Frontiers in Immunology, v.13, p. 1-15
ISSN
1664-3224
Start page
1
End page
15
Rights
Attribution 4.0 International

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